Infusion system for creating microenvironments in a living body

ABSTRACT

The invention provides implantable infusion systems, including apparatus and methods, for prolonged infusion of a carefully designed medicament composition to create and maintain a comprehensive microenvironment at a target area in a living body. The composition may include living cells to treat a particular disease and which deliver exogenous substances to maintain a microenvironment in the living body. The invention contemplates medicament compositions that include stem cells (neuro or otherwise), including homographs and allographs, adhesive peptides, substances which inhibit fiberblast growth, genetically modified cells which produce useful exogenous substances, nerve growth factor (NGF), previously harvested cells from a living body. In another aspect, the invention contemplates the replication of cells in a reservoir, for example, to keep cells alive in a dormant state until infusion.

[0001] This application is a continuation of, and claims priority to,U.S. application Ser. No. 09/303,033, filed Apr. 30, 1999.

FIELD OF THE INVENTION

[0002] The present invention relates to systems, including methods andapparatus, for delivering therapy to specific sites in a living body.More particularly, the invention relates to implantable infusion systemsfor creating and maintaining microenvironments in a living body toprovide therapeutic effects, including tissue regeneration andproduction of therapeutic agents for living tissue.

BACKGROUND OF THE INVENTION

[0003] Microenvironments are spaces, either in vitro or in vivo, whereinspecific conditions are controlled and maintained in order to obtainspecific therapeutic effects, including, for example, the promotion oftissue regeneration and the introduction or fostering of growth anddevelopment of living cells that generate particular therapeutic agents.It is widely recognized that the tissues of the Central Nervous System(CNS) have much less capacity for regeneration than other tissues in themammalian body. It has been suggested that the some tissues may lackcellular or substrate constituents that are conducive for growth duringdevelopment (Liesi, 1985, EMBO J. 4:2505-2511; and Carbonetto et al,1987, J. Neurosci. 7:610-620), or particular sites in the body maycontain components which are nonpermissive inhibitory for cellregeneration (Schwab and Thoenen, 1985, J. Neurosci. 5:2415-2423). As aresult, recent efforts have focused on the creation and maintenance ofmicroenvironments to aid in the repair of damaged or degenerated area ofthe CNS. These efforts include, for example, the introduction of stemcells into the target site, and are described, for example, byWhittemore et al, “Gene Therapy and the Use of Stem Cells for CentralNervous System Regeneration,” Advances in Neurology, Vol. 72, pp.113-119 (1997); Will et al, “Regeneration in Brain and Spinal Cord,”Cellular and Molecular Basis of Regeneration From Invertebrates toHumans,” pp. 379-397, Wiley & Sons (1998); and Stichel-Gunkel, “The Roleof the Microenvironment in Axonal Regeneration,” Advances in Anatomy,Embryology and Cell Biology 137, (1997). The entire writings of each ofthese references are incorporated herein by reference.

[0004] It is also known to utilize mechanical implements, such as nerveregeneration chambers, to define and maintain microenvironments in theimmediate vicinity of a damaged nerve in the human body to foster therepair and growth of the damaged tissue. For example, U.S. Pat. No.5,584,885, the entire writing of which is incorporated herein byreference, discloses a nerve regeneration chamber which maintains amicroenvironment to promote the regeneration of a damaged nerve. Theregeneration chamber includes injection ports and exhaust ports tosupply agents to the regeneration chamber and to remove agents from theregeneration chamber. Such techniques require additional implantationand associated trauma in order to place the regeneration chamber at thetarget site.

[0005] It is further known, as exemplified in U.S. Pat. No. 5,832,932 toprovide infusion systems for infusing therapeutic agents, in the form ofdrugs, to specific sites in the human brain to treat movement disordersand other diseases. However, known infusion therapy systems provide onlya limited range of non-living substances to treat a target area of theliving body and have not heretofore been used to create comprehensivemicroenvironments in a living body.

[0006] What is needed is an infusion system for delivering a carefullydesigned medicament composition for creating and maintaining acomprehensive microenvironment in a living body. Specifically, what isneeded is an implantable infusion system capable of providing a diverserange of medicament compositions, including living and non-livingsubstances, in order to create and maintain a desired microenvironmentin a living body for an extended period of time.

BRIEF SUMMARY OF THE INVENTION

[0007] The present invention solves the aforementioned problems byproviding a system for infusing a carefully designed medicamentcomposition to achieve a particular desired therapeutic effect. Thecomposition may include living cells to treat a particular disease andwhich deliver exogenous substances to maintain a microenvironment in theliving body. For example, stem cells may be provided in the compositionto be introduced into the living body and, in an appropriateenvironment, caused to mature into nerve cells once delivered to atarget site. The invention contemplates medicament compositions thatinclude stem cells (neuro or otherwise), including homographs andallographs, adhesive peptides, substances which inhibit fiberblastgrowth, genetically modified cells which produce useful exogenoussubstances, nerve growth factor (NGF), and previously harvested cellsfrom a living body. In another aspect, the invention contemplates thereplication of cells in a reservoir, for example, to keep cells alive ina dormant state until infusion.

[0008] Still another aspect of the invention provides a particulartreatment system for Parkinsonian patients in which stem cells areintroduced into the living body and provided with other factors thatencourage the cells to develop into dopamine-producing cells. Such cellsare introducing into the existing cell structure, which is used as aframework for cell growth.

[0009] Yet another aspect of the invention provides a particulartreatment system for patients who have experienced trauma to the CNS,where a carefully designed medicament composition is delivered to a gapin the nerve structure and newly introduced living cells fill the gap inan organized fashion providing a bridge for nerve impulses traversingthe gap, restoring peripheral neural control of distal structures.

[0010] The unique advantages provided by the invention have applicationto the rebuilding or regeneration of tissue structures including nerves,bone, cartilage, tendons and organs. The prolonged infusion of acarefully designed composition operates to foster the development oftissue in cases, for example, where a living body has inadequateresources to provide for regeneration on its own. The invention is alsoadvantageous in providing a comprehensive medicament compositionincluding living cells and the substances required to sustain the lifeof those cells, to provide a microenvironment that produces therapeuticagents, such as dopamine in applications for treating Parkinsonianpatients.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] These and other advantages and features of the invention willbecome apparent upon reading the following detailed description andreferring to the accompanying drawings in which like numbers refer tolike parts throughout and in which:

[0012]FIG. 1 is a plan view of an exemplary system according to theinvention, shown implanted in a living body;

[0013]FIG. 2 illustrates an exemplary system according to the invention,for infusing a medicament composition to a target area in a human brain;

[0014]FIG. 3 is a block diagram depicting an exemplary method oftreating Parkinsonian patients according to the invention; and

[0015]FIG. 4 is a block diagram depicting an exemplary method oftreating a traumatized target area of the CNS according to theinvention.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The As explained in more detail below, the present inventionovercomes the above-noted and other shortcomings of known systems byproviding an infusion system for delivering a carefully tailoredmedicament composition to create and maintain a comprehensivemicroenvironment in a target area of a living body for therapeuticeffect.

[0017]FIG. 1 illustrates an exemplary apparatus for accomplishing theinvention. A living body 10 is provided with an implanted infusiondevice 12, including at least one catheter 14 for conveying a medicamentcomposition from the infusion device 12 to a target area 16. The generaldetails of infusion device 12, which is preferably an infusion pump,modified to accommodate a desired medicament composition, are similar tothe SYNCHROMED pump developed by Medtronic. Such modifications mayinclude the elimination of “dead-end” volumes which might providepotential areas for cell aggregation. Moreover, the surfaces within thepump which are encountered by the medicament composition could be coatedwith materials that encourage cell preservation and inhibit cellaggregation. In accordance with the invention, infusion device 12 isprovided with one or more reservoirs for containing respectivemedicament compositions necessary for maintaining the desiredmicroenvironment at target area 16. One reservoir may contain livingcells while another would contain other factors which foster stem cellgrowth into a particular desired mature cell type. The pump couldincorporate features such as those described in U.S. Pat. No. 5,769,823,the entire writing of which is incorporated herein by reference. Theinvention also contemplates the use of plural implantable pumps, withone pump configured to deliver living cells and the other pumpconfigured to deliver factors which foster growth of those living cellsinto a particular desired mature cell type.

[0018] As used herein, the term “medicament composition” refers to anysubstance or mixture of substances, both living and non-living, whichprovide a therapeutic effect to the target area. Medicament compositionscontemplated by the invention include stem cells (neural progenitors,both homographic and allographic), neurotophic factors, includingproteins, nerve growth factors, genetically modified cells, includingthose which produce enzymes, co-factors, neurotransmitters and trophins,adhesive peptides and previously harvested cells from a patient.

[0019] The substances that constitute medicament compositions of theinvention fall within several categories of agents, including growthfactor agents, extracellular matrixes, and cell components. Growthfactor agents enhance or encourage the growth of tissues and may includeembryonic tissue cells, fluid from embryonic tissue cells, tissues andgenetically engineered agents, such as Nerve Growth Factor (NGF), whichhas been produced through genetic cloning. Extracellular matrixesinclude those agents which form surrounding materials, supportstructures or connective tissues, such as collagen, laminin, andfibronectin, which are basement membrane components of the extracellularmatrix or which provide directional clues guiding the growth orregeneration of the tissues, such as target derived neuronotrophicfactors. Cell components include those agents which form components ofthe regenerating tissues or tissue structures associated with theregenerating tissues. Cell components used in the regeneration of nervetissues, for example, may include Schwann cells, which comprise supportcells for nerve tissues, glial cells, and fibroblasts.

[0020] In the case of nerve regeneration, therefore, the possible agentsinclude neurite promoting factors, surface active agents, neurotrophicagents, humoral agents, and chemical agents causing or enhancing theregeneration process. Examples of such would include collagen, laminin,fibronectin, living cells including Schwann cells, glial cells, dorsalroot ganglia cells, neural crest cells and neural and supportive agents.Still further examples of possible agents would include, but not belimited to, nerve growth factor (NGF), ciliary neuronotrophic factor(CNTF), motor nerve growth factor (MNGF), neural cell adhesion molecules(N-CAM), N-Cadherin, fibrin, hormones such as estrogen, testosterone,thyroid hormone, corticotropin, and insulin, catalase, acidic fibroblastgrowth factor (aFGF), basic fibroblast growth factor (bFGF), forskolin,glia-derived protease inhibitor (GdNPF), ganglioside GM-1, insulin-likegrowth factor, isaxonine, leupeptin, muscle basal lamina pyronin, andHyaluronic Acid.

[0021] Those of ordinary skill in the art will recognize that the abovelisted medicament compositions are only exemplary and representative andare not intended to be a limiting definition of the possible medicamentcompositions that may be used in the regeneration process and that yetfurther medicament compositions may be defined for each form of tissueto be regenerated.

[0022] Referring to FIG. 2, in an exemplary application of the inventionfor treating Parkinsonian patients, a medicament composition of stemcells is delivered to the basal ganglia area of the human brain and,once they reach the target area of the basal ganglia, develop intodopamine-producing cells owing to the introduction of appropriatefactors. The distal end of catheter 14 may be implanted in a portion ofthe basal ganglia of the human brain using known implantationtechniques. The medicament composition stored in the reservoir ofinfusion pump 12 is delivered via catheter 14, at a controlled rate, tothe target site 16 in the human brain.

[0023] Referring additionally to FIG. 3, in accordance with anotheraspect of the invention, the infusion device 12 delivers a medicamentcomposition that includes living cells, which develop into cells thatnaturally produce dopamine once in the target area. In addition, themedicament composition is provided with substances which support celllife, such as cell nutrients or substances which influence or fosterparticular cell effluents. The native cell framework or existing cellstructure 18, within the target area 16, provides for the mechanicalsupport of the infused cells. In accordance with the invention, aconstant, prolonged microenvironment is provided through the livingcells infused to the target area, as well as the additionalcell-supporting substances provided in the medicament composition.

[0024] An exemplary system for treating a traumatized area of the CNS isillustrated in block diagram form in FIG. 4. Here, the microenvironmentis designed to encourage the bridging of nerve structures using newcells, connecting the distal and proximal sections of damaged nerves.Reconnection may be fostered using known techniques for axonalregeneration and synaptogenesis. Stem cells are conveyed via theinfusion device 12 to a gap 22 in the nerve cell structure in targetarea 16.

[0025] Those of ordinary skill in the art will recognize that theinfusion device 12 may require certain modifications depending on themedicament composition for which it is configured. For example, ifliving cells are incorporated into the medicament composition, theinternal components of the infusion device 12 would require modificationso as not to jeopardize the integrity of the living cells containedtherein. Such modifications may include the elimination of sharp ornarrow passages within the infusion device to avoid damage to cellularstructures. The invention contemplates providing for cell replication ina reservoir, for example, to maintain living cells in a dormant stateuntil infusion. For example, vitamin A derivative retinoic acid canstimulate stem cells to produce neurons, perhaps by interacting withstem cell receptors to foster the development of nerve tissue.

[0026] Those skilled in the art will recognize that the preferredembodiments described above may be altered or modified without departingfrom the true spirit and scope of the invention, as defined in theaccompanying claims.

What is claimed is:
 1. A system for creating and maintaining amicroenvironment in a living body, the system comprising: an implantableinfusion device for delivering a medicament composition to a target sitein the living body, the infusion device having a reservoir; a medicamentcomposition contained in the reservoir for providing a therapeuticbenefit to the target site, the medicament composition beingspecifically tailored to provide a comprehensive microenvironment at atarget site in the living body.
 2. The system of claim 1 wherein theinfusion device comprises an implantable infusion pump.
 3. The system ofclaim 2, wherein the medicament composition includes living cells. 4.The system of claim 2, wherein the medicament composition includes oneor more neurotropic factors.
 5. The system of claim 2, wherein themedicament composition includes stem cells that may be later modified toproduce an exogenous substance.
 6. The system of claim 5, wherein theexogenous substance is selected from the group consisting of enzymes,co-factors, neurotransmitters and trophins.
 7. The system of claim 1,wherein the reservoir is provided with means for maintaining the cellsin a dormant state.
 8. A method of treating a patient comprising thesteps of: implanting an infusion system in the patient, the infusionsystem including a reservoir for containing a first medicamentcomposition; operating the infusion system to deliver the firstmedicament composition to a target sight to thereby create amicroenvironment in the target site in the patient's body; and infusinga second medicament composition to foster the development of cells whichproduce exogenous substances at the target site.
 9. The method of claim8, wherein the step of operating the infusion system further comprisesthe step of delivering living cells to the target site.
 10. The methodof claim 9, wherein the step of operating the infusion system furthercomprises the step of utilizing native cell structures at the targetsite as a framework on which the living cells grow.
 11. The method ofclaim 10, wherein the living cells produce exogenous substances oncedelivered to the target area.
 12. The method of claim 8 wherein thefirst medicament composition is selected from the group consisting ofstem cells, neurotrophic factors, proteins, nerve growth factors,genetically modified cells, enzymes, co-factors, neurotransmitters,trophins, and adhesive peptides.
 13. A method of creating or maintaininga microenvironment in a living body comprising the steps of: implantingan infusion device in the living body, the infusion device having areservoir containing a medicament composition selected from the groupconsisting of stem cells, neurotrophic factors, proteins, nerve growthfactors, genetically modified cells, enzymes, co-factors,neurotransmitters, trophins, and adhesive peptides; delivering, via theinfusion device, the medicament composition to a target area of theliving body to create or maintain a microenvironment in the target area.14. A method of creating or maintaining a microenvironment in a livingbody comprising the steps of: implanting an infusion device in theliving body, the infusion device having a reservoir containing amedicament composition selected from the group consisting of stem cells,neurotrophic factors, proteins, nerve growth factors, geneticallymodified cells, enzymes, co-factors, neurotransmitters, trophins, andadhesive peptides; delivering, via the infusion device, the medicamentcomposition to a target area of the living body to create or maintain amicroenvironment in the target area, and infusing an exogenous substanceto foster the growth of cells at the target area.
 15. A method oftreating a patient whose nervous system has been traumatized, the methodcomprising the steps of: implanting an infusion system in the patient'sbody; operating the infusion system to create and maintain amicroenvironment in a target site in the patient's body to foster theregeneration of the patient's nervous system.
 16. The method of claim15, wherein the step of operating the infusion system further comprisesthe step of delivering a medicament composition including living cellsto the target site.
 17. The method of claim 15, wherein the step ofoperating the infusion system further comprises the step of deliveringthe living cells to a gap in the nerve structure.